Tissue adhesives have many potential medical applications, including wound closure, supplementing or replacing sutures or staples in surgical procedures, adhesion of synthetic onlays or inlays to the cornea, drug delivery devices, and as anti-adhesion barriers to prevent post-surgical adhesions.
Conventional tissue adhesives include fibrin sealants, cyanoacrylate based sealants, and other synthetic sealants and polymerizable macromers. Some of these conventional sealants are only suitable for a specific range of adhesive applications. For example, cyanoacrylate-based adhesives have been used for topical wound closure, but the release of toxic degradation products limits their use for internal applications. Fibrin-based adhesives are expensive, often need refrigerated storage, are slow curing, have limited mechanical strength, and pose a risk of viral infection.
For certain applications, for example, ophthalmic applications such as sealing wounds resulting from trauma such as corneal lacerations, or from surgical procedures such as vitrectomy procedures, abdominal hernias, cataract surgery, LASIK surgery, glaucoma surgery, and corneal transplants; neurosurgery applications, such as sealing the dura; plugging to seal a fistula or the punctum, slow degrading tissue adhesives are needed.
The last decade, several types of (semi)synthetic hydrogel tissue adhesives have been developed, which have improved adhesive properties and are non-toxic. Most of these hydrogel tissue adhesives, like DuraSeal™, are chemically based on a process called PEGylation used in polymer-modified therapeutics with polyethylene glycol (PEG) end capped mPEG-NHS precursors like, for instance, PEG-succinimidyl glutarate. These hydrogel tissue adhesives, based on PEGylation, typically swell or dissolve away too quickly, or lack sufficient cohesion (interconnecting mechanical strength), thereby decreasing their effectiveness as surgical adhesives. Moreover, to apply these hydrogel tissue adhesives, dual syringe spray technology may be needed, which demands extensive sample preparation from freeze dried starting materials. Finally, the properties of such PEG-based materials cannot be easily controlled and the number of NHS-groups is limited to the number of chain ends; possibly comprising multiple NHS groups per chain end resulting in a high NHS group density rather than regularly distributed groups.
WO 02/062276 describes a hydrogel tissue sealant comprising a star-shaped PEG-succinimidyl glutarate precursor, also known as star-PEG-NHS or star-PEG-NS or star-SG-PEG or star-PEG-SG, that reacts with a trilysine precursor. The star-SG-PEG precursor may be reconstituted in pH 4 phosphate, while the trilysine precursor may be reconstituted in pH 8 borate buffer. Upon mixing, covalent amide bonds between amines of the trilysine precursor and NHS-activated terminal carboxylate groups of the star-SG-PEG precursor are formed.
US 2003/0119985 and US 2005/0002893 describe a tissue sealant based on the same star-PEG-NHS/trilysine principles in which hydrogels are formed by reacting a component having nucleophilic groups with a component having electrophilic groups to form a cross-linked network via covalent bonding.
WO 2010/043979 describes an implant comprising: a porous layer, said porous layer comprising a first sublayer that comprises a first hydrogel precursor and a second sublayer free from hydrogel precursor; and a first additional layer, said first additional layer being a non porous layer comprising a second hydrogel precursor, wherein the first hydrogel precursor has nucleophilic functional groups and the second hydrogel precursor has electrophilic functional groups.
WO 02/102864 describes cross-linkable composition comprised of:    a) a first cross-linkable component A having m nucleophilic groups, wherein m>2;    b) a second cross-linkable component B having n electrophilic groups capable of reaction with the m nucleophilic groups to form covalent bonds, wherein n>2 and m+n>4; and    c) a third cross-linkable component C having at least one functional group selected from (i) nucleophilic groups capable of reacting with the electrophilic groups of component B and (ii) electrophilic groups capable of reacting with the nucleophilic groups of component A, wherein the total number of functional groups on component C is represented by p, such that m+n+p>5wherein at least one of components A, B and C is comprised of a hydrophilic polymer, and cross-linking of the composition results in a biocompatible, nonimmunogenic, cross-linked matrix. Polyoxazolines are mentioned as an example of a hydrophilic polymer.
WO 2006/078282 describes a dry powder composition comprised of: a first component having a core substituted with m nucleophilic groups, where m>2; and a second component having a core substituted with n electrophilic groups, where n>2 and m+n>4; wherein the nucleophilic and electrophilic groups are non-reactive in a dry environment but are rendered reactive upon exposure to an aqueous environment such that the components inter-react in the aqueous environment to form a three-dimensional composition. The core of the first or second component can be a hydrophilic polymer. WO 2006/078282 mentions a range of different hydrophilic polymers, including polyoxazolines.
WO 2010/033207 describes a conjugate comprising a residue of a therapeutic peptide moiety covalently attached, either directly or through a spacer moiety of one or more atoms, to a water-soluble, non-peptidic polymer. Polyoxazoline is mentioned as an example of a water-soluble polymer.
WO 2009/043027 describes multiarmed, monofunctional forms of polyoxazolines and conjugates of such polyoxazoline derivatives with drugs. Example 18 describes the coupling of bis-amine with a polyoxazoline with the repeating unit having the structure —[N(COCH2CH3)CH2CH2]n—, in which the terminal nitrogen is bound to methyl and in which the other terminus carries the following electrophilic residue: —OCO2—NHS.
U.S. Pat. No. 5,635,571 describes polyoxazolines comprising a terminal NH2 or OH group and a pendant ester group. A hyperbranched polymer is produced by amidation between the pendant ester group and the chain terminating NH2 or by transesterification between the pendant ester group and the terminating OH group.
Chujo et al. (Reversible Gelation of Polyoxazoline by Means of Diels-Alder Reaction, Macromolecules, 1990 (23), 2636-2641) describes the preparation of a polyoxazoline hydrogel by means of intermolecular Diels-Alder reaction between furan-modified poly(N-acetylethylenimine) (PAEI) and maleimide-modified PAEI, which were synthesized from the partially hydrolyzed PAEIs by the reaction with furan- or maleimidecarboxylic acid, respectively, in the presence of dicyclohexylcarbodiimide.
Luxenhofer (Thesis: Novel Functional Poly(2-oxazoline)s as Potential Carriers for Biomedical Applications, Technische Universitat Munchen (2007)) describes poly(2-oxazoline) hydrogels. These hydrogels are prepared by crosslinking a poly(2-methyl-2-oxazoline) comprising aldehyde sidechains with hydrazine or with a poly(2-ethyl-2-oxazoline) comprising amine sidechains. Gelation and swelling was evaluated in aqueous buffers having a pH in the range of 4 to 9.
It is of interest to expand the range of polymers having implant or tissue sealant applications, especially to provide polymers having properties not possessed by PEG-based polymers while being similarly biocompatible.